This Phase II application is being submitted in response to a continuing NIMH program announcement for Pharmacological Agents and Drugs for Mental Disorders. The goal of the proposal is to use an innovative behavior-driven approach to psychiatric drug discovery to overcome the major limitations associated with target-driven approaches that have impeded the discovery of new and improved medications. In Phase I, we applied the SmartCube. high throughput, automated, in vivo discovery platform and used it to demonstrate that an efficient and powerful behavior-based system can be used as a primary screen to identify novel hits for the treatment of psychiatric disorders. That approach proved to be extremely successful as we already have identified 125 SmartCube hits. Ten of these have novel and diverse target profiles and their therapeutic potential for treating depression, psychosis, or anxiety has been confirmed in multiple standard behavioral assays. In Phase II we will demonstrate that SmartCube. can be used to enable behavior-driven lead optimization and use it to advance three of our most interesting and novel lead compounds to become clinical candidates. This will be accomplished by using SmartCube in combination with state of the art computational chemistry and capitalizing on the rapidly growing availability of commercial analogs. It will involve 1) thorough characterization of key in vitro and in vivo drug-like properties of these compounds including oral bioavailability, chronic efficacy, in vitro metabolic stability, in vitro cardiotoxicity and in vitro genotoxicity to identify properties that need to be optimized; 2) exploring the mechanism of action of the two most novel lead compounds; 2) creating a Structure Activity Relationship for behavioral activity with computational tools and commercially available analogs; 3) synthesizing focused series of novel analogs predicted to have desirable drug-like properties under the guidance of experienced medicinal chemists; 4) screening these analogs in SmartCube and then demonstrating improvement in key features; and finally; 5) testing the most promising compounds in toxicity assays in order to select an Early Development Candidate (EDC). Our goal is to advance 1-3 promising drug candidates for psychiatric disorders and demonstrate that this unique, behavior-driven approach to CNS drug discovery is feasible using our proprietary technology. This innovative approach is unique in the industry and has the potential to significantly reduce both the time and cost of psychiatric drug discovery. [unreadable] [unreadable] [unreadable]